Dual antiplatelet therapy is the mainstay of medical treatment after percutaneous coronary intervention regarding the risk of stent thrombosis occurrence. Since the beginning of the stenting era, antiplatelet regimens have evolved according to the emerging and widespread diffusion of new devices and more challenging indications for their use. In the past years, concerns have been raised about the safety of drug-eluting stent implantation with regard to late and very late stent thrombosis. Thus, the length of dual antiplatelet therapy has been progressively increased with marked individual and local differences. However, prolonged antiplatelet therapy leads to increased risk of bleeding, especially in the setting of surgical procedures, traumas, and/or other diseases. To date, the exact duration of dual antiplatelet therapy after drug-eluting stent implantation is still debated in the literature. The aim of this article is to review the literature and the current guidelines on the risks and benefits of pursuing dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stent implantation.